Journal
CELL REPORTS
Volume 21, Issue 11, Pages 3205-3219Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.11.063
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Funding
- Wilhelm Sander-Stiftung (Munchen) [2014.107.1]
- German-Israeli Foundation (Jerusalem) [I-188-414.3-2014]
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Adoptive therapy with chimeric antigen receptor (CAR)-redirected T cells has achieved remarkable efficacy in the treatment of hematopoietic malignancies. However, eradicating large solid tumors in advanced stages of the disease remains challenging. We explored augmentation of the anti-tumor immune reaction by establishing an acute inflammatory reaction. Systematic screening indicates that IL-18 polarizes CAR T cells toward T-bet high FoxO1 low effectors with an acute inflammatory response. CAR T cells engineered with inducible IL-18 release exhibited superior activity against large pancreatic and lung tumors that were refractory to CAR T cells without cytokines. IL-18 CAR T cell treatment was accompanied by an overall change in the immune cell landscape associated with the tumor. More specifically, CD206(-) M1 macrophages and NKG2D + NK cells increased in number, whereas Tregs, suppressive CD103(+) DCs, and M2 macrophages decreased, suggesting that iIL18 TRUCKs'' can be used to sensitize large solid tumor lesions for successful immune destruction.
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